Updated

Testing negative for the BRCA2 gene mutation doesn’t necessarily mean a women isn’t still at high risk for developing breast cancer.

In a new study published in Cancer Epidemiology, Biomarkers and Prevention, researchers from the University of Manchester in England revealed that women who come from families with BRCA2 mutations are still at a greater risk for developing breast cancer – even if they test negative for the BRCA2 gene themselves.

Mutations in the BRCA1 and BRCA2 genes have long been known to increase a woman’s risk for developing breast and ovarian cancer. The BRCA genes produce tumor suppressor proteins that help repair damaged DNA, so when these genes are faulty, genetic damage can accumulate in the body.

Recently, Angelina Jolie shed light on BRCA mutations in an Op-Ed written for the New York Times, in which she revealed she had undergone a double mastectomy after testing positive for a mutation in the BRCA1 gene.  She also noted that the mutation meant that her risk of developing breast cancer was 87 percent. But according to study author Dr. Gareth Evans, her risk had a much wider degree of variability.

“Your risk of developing breast cancer is only partially driven by carrying the mutation,” Evans, honorary professor of medical genetics and cancer epidemiology at the Manchester Academic Health Science Center at the University of Manchester, told Foxnews.com.  “In no way am I trivializing the risk, but one woman may have a 45 percent risk and another might have 87 percent risk – where the rest might be driven by lifestyle factors.”

Strong evidence has shown that other inheritable genetic risks factors can raise or lower a person’s risk for cancer.  According to Evans, there are approximately 77 single nucleotide polymorphisms (SNPs) that women can inherit, which have been identified as contributing  to their breast cancer risk, and the wrong combination of these SNPs can greatly enhance their chance of developing disease.

“So even though you may test negative for the fault in BRCA1 and BRCA2 you may still inherit a bad combination of these other factors,” Evans said.  “So if you have a strong family history, that means you may have inherited some of this other genetic shrapnel that puts you at increased risk.”

In order to verify this, Evans and his team utilized data form the M6-Inherited Cancer in England study, which screened families of individuals with breast and/or ovarian cancer for mutations in the BRCA1 and BRCA2 genes.  The researchers analyzed 807 BRCA families and identified 49 women who tested negative for their family-specific BRCA mutation – but still went on to develop breast cancer.

Of these 49 women – whom the researchers referred to as phenocopies – 22 tested negative from BRCA1 families and 27 tested negative from BRCA2 families.  To conduct risk analyses of the phenocopies, the researchers calculated an “observed versus expected” ratio (O/E) – which measured the ratio of observed risk for breast cancer in BRCA-negative women from BRCA families, versus the breast cancer risk for women in the general population.

While the O/E for phenocopies from BRCA1 families was not substantially higher than the general population, the O/E for phenocopies from BRCA2 families was 4.57 – equating to a more than fourfold increased risk of developing breast cancer than the general population.

“So if you’re a first degree relative in a family with a BRCA2 mutation, and you have two close relatives with breast cancer at a young age, you should still be considered at moderate to high risk for developing breast cancer,” Evans sad.  “If you come from a family that has no breast cancer history, and you test negative, you should be reassured.”

Evans said specialists should use caution when saying that women who have negative BRCA tests have the same breast cancer risk as the general population.

“Just be aware that you may still be at some increased risk of breast cancer, even if you’ve tested negative for the gene,” Evans said.